Fighting with a Killer. ( Lung Cancer)

Lung Cancer

PKGhatak,MD

Lung cancer is a fatal illness. Incidence and deaths from lung cancer are steadily increasing in developing parts of the world, as they did in the West after the end of WWII and the incidence of new cases of lung cancer is directly related to cigarette smoking and industrialization with the degradation of the environment.

Basically, there are two classes of lung cancers.

1. Small cell lung cancer.

2. Non-small cell lung cancer. (NSCLC)

The above classification is based not only on the pathological features of the cancer cells but also applies to symptomatically, tumor spread, response to therapy and prognosis.

Susceptible population.

Adults with a long history of cigarette smoking, working in places where air or soil or water is contaminated with radioactive elements, those who are carriers of BRACA 2 gene, survivors of leukemia and other malignancy, and those who received chest radiation, people receiving immunosuppression therapy following organ transplants or having autoimmune diseases are susceptible for lung cancer. Incidences are also higher in patients with a certain type of pulmonary fibrosis and scar tissue in the lung. Exposure to radon gas and asbestos are recognized risk factor. Exposure to heavy metals, specially arsenic, is carcinogenic. A higher incidence in Sarcoidosis is a risk factor.

Symptoms at the time of Presentation.

Patients may not have any symptoms and cancer is incidentally detected when a chest X-ray was taken for other reasons. In the early stages, in symptomatic patients, an unproductive cough is usual. Some patients develop asthma for the first time in midlife. Some patients seek help when they coughed up bright red blood. Other symptoms are as follows. -  Feeling vague symptoms of not feeling well, unintended weight loss, hoarseness of voice, lump in the neck area, weakness of large muscle groups of hips making getting up from bed or chair difficult and then the weakness of shoulder muscle limits patients' ability to raise hands overhead - Lambert-Eaton syndrome. Unexplained neuritis of one or more peripheral nerves in different parts of the body. Pain over spinal bones or ribs. Some have convulsions as first the presenting symptoms. Clubbing of fingers, pretibial edema and tenderness over lower tibial bones. Deep vein thrombosis,  neuromusculopathy, peripheral neuritis and dermatomyositis are also presenting symptoms.

Special features of Small Cell Cancer. 

Small cell carcinoma is only 15 % of the total lung cancer population. Under the microscope, the cancer cells resemble carcinoid cells. There is a very strong correlation with cigarette smoking. Patients are often male and in middle aged group. The common symptom which brings them to doctors is chest pain which is often mistaken for heart attacks or angina. Initial routine chest x-rays often appear normal. Either by CT scan of the chest or very expert radiologists can detect a faint outline of a tumor on chest x-rays, located on the upper lobe of the lung and in the hilar region.

Early hilar lymph node enlargement produces pressure symptoms on the local structures. As more tissues are infiltrated by tumor cells, and more symptoms develop this is called Thoracic Inlet syndrome, the symptoms of Thoracic Inlet syndromes are A. 1. Inferior cervical ganglion and paravertebral sympathetic chain infiltration by cancer cells produce a dropping of the upper eyelid with 2. a small constricted pupil and 3. loss of sweating on the involved side of the forehead. This symptom complex is called - Horner syndrome.

 B. Pain in the arm and forearm in the distribution of brachial plexus nerves.

 C. Superior vena cava obstruction producing edema of head and neck, bluish discoloration of face, distended conjunctival vessels.

 D. Infiltration may include the phrenic nerve producing paralyzed hemidiaphragm.

E. Infiltration of apical pleura may produce pruritic chest pain and pleural effusion.

Paraneoplastic syndrome. The small cell cancer cells and rarely alveolar cell cancer, at times, secrete hormones like polypeptides and produce a variety of symptoms. A few of them are mentioned here.

Cushing's syndrome is due to excess ACTH secretion. Hyperparathyroidism produces high serum calcium and symptoms related to it. TSH like hormone secretion leads to thyrotoxicosis. Insulin like hormone produces severe hypoglycemia. Melanin like peptide producing Acanthosis nigricans - dark pigmentation of skin in intertriginous areas and the flexural surface of limbs. Severe hyponatremia due to inappropriate antidiuretic hormone production (ADH) causes excess free water reabsorption in renal tubules.

 Tumor cell behavior.

Tumor cells spread early and often by the bloodstream to the brain and bones.

Biopsy.

Fine needle aspiration biopsy under ultrasound guidance yields good results. Often bone marrow biopsy is required for diagnosis and staging. The cancer cells are small and rounded with a thin margin of peripheral cytoplasm, and coarse chromatin without a nucleolus. The cytoplasm contains neurosecretory granules in 90 % of cases. No immunological staining is possible. 

Treatment.

In the localized early stage of the disease, chemotherapy containing Cisplatin or Carboplatin and Etoposide followed by cranial radiation is recommended. In widespread diseases, a combination of chemotherapy and chest radiation therapy is followed by cranial radiation is done. No immunotherapy drug has any role in the treatment of small cell cancer.

 

Prognosis.

The 2-year survival rate in late presentation is disappointing, only 2 to 5 %, and 20 to 40 % in early cases.

Non-Small Cells Lung Carcinoma (NSCLC).

 

This group contains Adenocarcinoma, Squamous cell carcinoma, Large cell carcinoma, alveolar cell carcinoma and others.

 

Special features of NSCLC.

85 % of all carcinoma of the lung fall into this group, and adenocarcinoma leads this group.

Nonsmokers and smokers, unfortunately, are both susceptible to Non-Small Cell cancer of the lung. Malignant transformation of squamous dysplasia, a common occurrence in smokers, into squamous carcinoma is a usual occurrence. Adenocarcinoma may develop from preexisting scars. Delayed clearing of pneumonia, bloody sputum, or associated pleural effusion may be the presenting symptoms. High serum calcium is often seen in squamous cell carcinomas from osteolytic bone metastasis. Seizures from single brain metastasis are seen in adenocarcinomas. Early metastasis via blood is common in adenocarcinomas. Hypertrophic Pulmonary Osteodystrophy (HPO) is often seen. The HPO is characterized by burning pain and red discoloration of the skin over the tibia and knees, edema, clubbing of fingers, and tender wrists and fingers due to subperiosteal new bone formation. Squamous cell carcinomas are usually centrally located and produce hemoptysis. Adenocarcinomas are usually located at peripherally and arise from mucus glands and or from the epithelial cells of terminal bronchioles.

Alveolar carcinomas are included in the adenocarcinoma group but it has some distinct features - generally have multiple sites of origin, patients have vague symptoms that can go on for a significant time period; patients often develop neurological symptoms or psychological problems. The diagnosis is often delayed because sputum examinations generally are free of cancer cells and the tumors are not accessible to bronchoscopic view. A lung biopsy is required for diagnosis.

Large cell cancers are rapid growers, maybe central or peripheral in location.

 

Diagnosis.

Bronchoscopy and bronchoscopic biopsy of the lesion are preferred. If the tumor mass is not accessible by bronchoscopy, then ultrasound guided fine needle aspiration biopsy is recommended. In cases where hilar lymph nodes are present,  suprasternal mediastinoscopy is preferred for biopsy and staging.

Immunohistochemical staining of biopsy helps the identification of cell types and subtypes.

The initial diagnosis is followed by the detection of mutation genes or genes which have great importance in the treatment with immunotherapy and the use of immunotherapy improves survival.

 

Treatment.

Surgery is the preferred treatment modality in all cases of NSCLC wherever possible. Surgery is followed by chest radiation therapy in localized disease without lymph node involvement.

In the case of lymph node involvement or evidence of distant metastasis Chemotherapy and radiation therapy are added after surgery. Chemotherapy agents are Platin based, most institutions follow their own protocols but all protocols include platins.

Prognosis of NSCLC and Immunotherapy.

The patients live 2 to 5 years following surgery and when combined with chemotherapy and /or radiation patients may live an additional 10 to 24 months.

Immunotherapy has added a new line of cancer therapy with good to excellent results in patients who were dimmed too far advanced or did not respond adequately to surgery and chemo-radiation therapy.

Immunotherapy:
Epidermal Growth Factor Receptor blockers, Tyrosine Kinase blockers, PD1, PD-L1 antibodies, CTLA 4 receptor blocking antibodies are available. These are briefly mentioned here.

Epidermal Growth Factor (EGF) – EGF is a protein first detected in the submandibular salivary and parotid glands. It promotes tissue repair, cell growth, and wound healing of the mouth, stomach and intestine. Subsequently, a group of proteins, similar in structure and functions was also found in many other tissues including immune cells. EGF binds with its receptors on the cell surface and then induces Tyrosine kinase - a key to the cell division, growth, and development of normal tissue. The gene that controls EGFR (epidermal growth factor receptor) can mutate and this leads to greatly increased receptors on the cell surface that result in excess cell growth. This is particularly seen in some cases of non-small cell cancer of the lung. Antibodies to EGFR are now available for treatment. The antibodies block EGFR receptors present on the cancer cell surface and prevent binding with ERGF and thereby preventing the progression of cancer.

 

Program Cell Death Protein 1(PD 1) is another cell growth regulating protein. This is a surface protein abundant on T cells surface. When it binds with its receptors, it down regulates immune response to foreign agents or cancer cells. Another transmembrane protein is Programmed death Ligand 1 (PD-L1). When PD-L1 binds with PD1 receptors, it performs dual functions. 1. reduces antigen-specific T cells in lymph nodes. 2. decreases apoptosis (programmed cell death) of normal T cells. Thereby reduces immunologic reactions. Non-small cell cancer of the lung has a rich supply of PD-L1 receptors and thereby evades Killer T cells and cancer progresses unchecked.

 

CTLA4 (cytotoxic T lymphocyte protein 4) is also called CD152, is a protein receptor, when binds with CD80 and CD86 it down regulates immune reactions and when binds with CD 28 it up regulates immune responses. Blocking antibody is available against CTLA4 and when combined with PD1 or PD-L1 antibody therapy the results are much superior to those used alone.

Unfortunately, immunotherapy also has adverse side effects. The immune cells can attack the skin, lungs, liver, nervous system, heart and kidneys and other organs. In such an instance, the immunotherapy has to be terminated.

 

Prognosis of non-small cell Lung Cancer.

The prognosis of lung cancer is not good. The 5-year survival is 18 %. Immunotherapy has greatly improved survival time in those who have the appropriate mutation of gene/ genes.

 

In the 13 August 2020 issue of the New England Journal of Medicine, an article on lung cancer clearly shows the declining incidence of lung cancer since 2001 and more impressive is the decline in the death rates. In the case of NSCLC, these results are due to the combined effects of decreased cigarette smoking in the USA population and the availability of immunotherapy drugs. The rate of decline of death rates nearly doubled from 2013 to 2016 when compared with the decline rate of new cases of lung cancers; conforming to the effectiveness of immunotherapy. In the case of small cell carcinoma, the decline in mortality is entirely due to a decrease in cigarette smoking, since immunotherapy for small cell cancer is not available.

In recent years, far advanced lung cancer cases many centers are treating patients with Chemotherapy plus Immunotherapy without looking into PD1 or other gene mutations. This practice is now extended to Small Cell cancer patients also. According to them, this combination showed improved survival time. However, it should be noted it is a palliative treatment.

If nothing else can convenience you, this study should. Do not doubt the benefits of giving up cigarette smoking. If you want to live a long life, this gives you one more chance. As an ad for satellite TV says " so, what are you waiting for"

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Mutation of Genes and Psoriasis

 

Genetic Mutation and Psoriasis

      PKGhatak,MD

Every function of the cell, from the time of conception to the very end of life, is guided by the instructions inscribed in the genes. These functions can be grouped as Innate, adaptive and aberrant.

The skin is a large and special organ. It is entirely exposed to the elements of the outer world (except the parts we intentionally keep covered by clothing). The surface layers of the skin must be replaced at a constant and consistent rate as they are lost and that is the Innate function; some of the cell functions have to be modified according to the changes in the external environment and changes in the body from infections, other diseases or nutritional causes and these are adaptive function. The aberrant functions are due to the mutation of genes and Psoriasis is one of them.

In psoriasis, the cells of the surface layer of the skin grow at a rapid rate and the new cells accumulate over the older cells before the old cells have time to fall off. The accumulated patches are called Plaques. Inflammatory cells infiltrate the skin and underneath the plaques, the blood vessels multiply in numbers causing an increase in the blood supply producing itching. The top layer of dead cells of the plaques appears as pale white to silvery flakes and dandruff on the scalp and is shed off easily. These plaques may be present over the elbows, knees, lower back, scalp and face. It may appear as pink or red scaly drop like lesions in children and is known as Guttate psoriasis. Plaques underneath the breasts, buttocks, and groins are called Flexural psoriasis. In some cases, the entire skin is covered with dead loose cells and the color of the skin turns red from the increase in blood supply and this is called Erythrodermic psoriasis. Lesions on palms and soles of feet appear as pustules called Pustular psoriasis. Psoriasis also affects nails and joints and is called psoriatic arthritis.

Study methods.

Study of families of multiple members affected by psoriasis, studies of affected twins, and analysis of whole genome for the presence of mutations of genes in psoriasis patients, methylation of genes which modify gene functions without altering DNA sequence are commonly employed methodologies to investigate the role of hereditary and or phenotype mutation of genes in psoriasis.

The mutation of gene/genes in T-lymphocytes and B-lymphocytes leads to altered functions of Interleukins and Cytokines. These interrelated changes ultimately alter the rate of cell divisions and programmed cell deaths, inflammatory responses and generate autoimmune diseases.

Over 80 mutated genes are associated with psoriasis. However, the genetic mutation in psoriasis in not more than 20 % of all cases of psoriasis. The cause of the rest is unknown. Investigators advanced various theories from poison to pollution of the environment but definitive evidence is lacking.

Reports from Saudi Arabia indicate 5 % of the adult population suffers from psoriasis. The prevalence of adult psoriasis in China is 0.5 %, in Norway-11 %, in USA -3 %, black to white- 3 to 1 ratio, in India -2%, in Western Europe -3 %, and in Latin America 2%.                 

Known gene mutation.

Mutated genes associated with psoriasis are called PSORS and are designated 1 through 9 numerically. These genes are present on Chromosomes 1 to 22, of which frequent mutation was seen in chromosomes nos.1.6,9,17 and 19. These mutations may be at one locus or in multiple loci. In the Chinese population mutation of genes on chromosome 1 is most frequent, in Europe, the mutation is frequent on chromosome 17. Studies in Saudi Arabia show autosomal dominant inheritance with mutation of a gene on chromosome 17 q25 (on the long arm of chromosome at band location 25) and q4 loci.

Human leukocyte antigens (HLA) B-13, B-17, B-57, and CW6 are associated with psoriasis. About 70 % of HLA mutation is due to HLA CW6.

Interleukin-36 amplifies TH-17 lymphocytes.

Gene-wide association (GWA) identified 16 loci. CD4 helper T cells and CD8 cytotoxic T cells are associated with psoriasis.

Genetic mutations alone may not by themselves be the cause of psoriasis but in association with additional factors are responsible for psoriasis. Publications from WHO indicate infections, poisonous agents in the air and water, stress, obesity, cigarette smoking, and concurrent autoimmune diseases- special Crohn's disease are triggering factors. All these factors, namely genetic predisposition, and hereditary and triggering factors lead to internal changes in the body and lead to the development of the chronic inflammatory autoimmune disease - psoriasis.

 

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